Objective To investigate the effect of perindopril combined with L-carnitine on exercise tolerance in patients with heart failure. Methods A total of 96 patients with heart failure admitted in our hospital from January 2018 to October 2019 were subjected in this study. They were divided into control group (perindopril) and observation group (perindopril and L-carnitine), with 48 cases in each group. In 3 d after the end of medication, the efficacy related indicators, including cardiac function, oxidative stress index, inflammatory index, and the results of 6-minute walking distance and cardiopulmonary exercise test were compared between two groups before and after treatment. SPSS statistics 19.0 was used for statistical analysis. Data comparison between two groups was perfomed usingχ² test or t test depending on date types. Results On the 3rd day after medication, the observation group had significantly lower left ventricular end-diastolic diameter, brain natriuretic peptide, mean arterial pressure, heart rate, blood lactate level and serum uric acid level, but higher urine 24-hour volume and tissue blood oxygen staturation when compared with the control group (all P<0.05). Higher levels of superoxide dismutase and glutathione peroxidase but lower malondialdehyde were seen in the observation group than the control group at 3 d after medication (all P<0.05). The levels of IL-6 and IL-10 were obviously decreased in both groups after treatment, and those in the observation group were remarkably lower than those in the control group (all P<0.05). On the 3rd day after treatment, the peak metabolic equivalent (MET_peak), peak metabolic equivalent percentage of predicted value (MET_peak% pred), peak oxygen consumption percentage of predicted value (VO_2peak%pred), and MET at the anaerobic threshold, VO_2peak, and 6-minute walking distance were significantly higher, while ventilation and carbon dioxide output were obviously lower in the observation group than the control group (all P<0.05). Conclusion Perindopril combined with L-carnitine has a good efficacy in the treatment of heart failure. It can improve heart function and exercise tolerance in the patients, which might be associated with oxidative stress and inflammation response.